Download A food and drug administration primer (1)

yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project

Document related concepts
no text concepts found
Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 55, No. 1, February 15, 2006, pp 4 – 8
DOI 10.1002/art.21711
© 2006, American College of Rheumatology
A Food and Drug Administration Primer
Given the recent series of events regarding the Food and
Drug Administration (FDA), including issues associated
with the withdrawal of rofecoxib and the subsequent removal of valdecoxib from the market, as well as issues
surrounding some of the newer biologic agents for the
treatment of multiple sclerosis, it seemed like a propitious
time to provide an article about the FDA and how it works.
I served as a Director of the division at the FDA that was
dedicated to evaluating the safety and efficacy of new
drugs in the treatment of pain and inflammation. This job
was remarkable because it afforded me the opportunity to
think about issues such as the relative safety of new and
older medications; issues regarding trial design, recruitment of patients, and inclusion and exclusion criteria; and
why some trials are successful whereas others fail. I remain grateful to have been afforded the opportunity to
serve the community in this manner, and as a result, I am
in a unique position to write an article describing how the
FDA works.
A Brief History of the FDA
The issue of relative risk to relative benefit is what drives
the work of the medical officer at the FDA. The fact that the
FDA is a unionized shop that also serves as a Washington
bureaucracy should describe for the reader a rather regimented workplace, with offices assigned according to seniority and pay grade, and with the work day defined to
provide regulatory oversight of therapeutics in the US.
Drugs are approved for interstate transport by authority of
the Food Drug and Cosmetic Act. Although many managed
care organizations and other groups such as formularies
use FDA approval as an important threshold for deciding
whether to reimburse for a therapeutic, the FDA does not
regulate medical care in the US. This concept of approval
was initially considered at the beginning of the 20th century with the development of the Pure Food and Drugs Act
and was precipitated by a series of deaths due to certain
contaminated foods (1). It was clear that something had to
Lee S. Simon, MD: Harvard Medical School, Beth Israel
Deaconess Medical Center, Boston, Massachusetts.
Address correspondence to Lee S. Simon, MD, Associate
Clinical Professor of Medicine, Harvard Medical School,
Beth Israel Deaconess Medical Center, 110 Francis Street
4B, Boston, MA 02115. E-mail: [email protected].
Submitted for publication November 10, 2005; accepted
November 10, 2005.
be done to protect Americans from impure foods, but what
would be legislated should not be enough to restrict free
trade in a democratic and capitalistic nation. This new law
specifically “prohibited interstate commerce in misbranded and adulterated foods, drinks, and drugs” and
required truth in labeling of substances covered by the law
Then in the late 1930s, another scandal rocked the nation. This time dozens of children died when prescribed
an antibiotic elixir that was contaminated. This led to the
Food Drug and Cosmetic Act of 1938, which superseded
the 1906 law and required that drugs and food be safe; the
contents would be adequately described in the product
label, but no explanation was offered as to how these
products were to be proven safe. Clinical trials as understood in the modern sense were not required to provide
this information. It was expected that the safety information would be extensively detailed in a product label,
which would also describe what was known about the
chemistry of a product (1,3).
In 1951, the Durham-Humphrey Amendment defined
“the kinds of drugs that cannot be safely used without
medical supervision and restricts their sale to prescription
by a licensed practitioner (3).” Therefore, the concept of
prescriptive drugs was officially born and led to the concept of prescriptions, which was meant to distinguish
over-the-counter or generally available drugs from therapeutics that needed a learned intermediary to describe
how to use the product (1).
The requirement for adequate and well-controlled trials
to prove efficacy and safety of products was not established until 1962. This modern approach was integrated
into the normal daily routine at the FDA, and it continued
in that manner until several changes took place in the
1990s. Prior to some modernization in the 1990s, a review
of a newly submitted product could take a very long time,
and the drug development companies had been lobbying
for years to accelerate this process. The appropriation from
Congress that supported the activities of the FDA was
limited, and consideration was given to the development
of a user fee that would be used to secure the appropriate
staff to allow for a much tighter timeline for review. A
sponsor of a new therapeutic would pay a user fee to the
government to help support the services provided to the
industry; this money was then funneled back to the FDA.
A user fee system (Prescription Drug User Fee Act
[PDUFA]) was implemented. This act required that the
FDA Primer
FDA perform to certain standards. Specifically, 90% of
standard reviewed drugs had to be fully reviewed within
10 months of submission. In addition, drugs that were very
important because of either a new mode of action or targeting of an unmet medical need would be reviewed more
quickly as a priority, and in 90% of these cases the review
would be finished in 6 months. This has led to a significant
change in the length of time for approval for many products, making them available more quickly (1).
The user fee act, which requires a payment of ⬎$600,000
per application for a full review, has had significant
impact on the FDA. The FDA has been able to hire an
increased staff for review, as well as to perform other
components of the daily work load. There are specific
statements in the user fee act regarding access to meetings
with the FDA and significant effort to increase the communication and interaction between a sponsor of the product and the FDA. Overall it provides for increased opportunities. However, there has been some suggestion
recently that this increased opportunity has led the FDA to
be less unbiased in its interpretation of evidence and perhaps to become too lax in review, allowing dangerous
drugs with little benefit to reach the marketplace. This is
an interesting proposition and sound bite for the media,
but falls flat when one considers the issues. The user fee is
paid to the government in general, and is still appropriated
by Congress given the performance of the FDA. Furthermore, there is very good evidence demonstrating that these
new safety issues observed in “real world” use are more
reflective of the limitations of the review process than the
coziness of industry and the FDA. Many of the safety
signals recently identified emerged in longer-term trials of
a large number of patients. Most approval data sets are
usually representative of shorter-term trials, and most databases represent ⬍3,000 exposed patients. To understand
some of these safety signals, many more patients need to
be exposed for far longer than is possible given the present
constraints of preapproval drug development strategies of
the industry, which are designed to meet the prevailing
requirements at the FDA. Phase IV studies and postapproval pharmacovigilence are critical parts of the strategy
for understanding the safety of all approved agents because a larger population of patients is typically observed
in that arena, especially patients with comorbid illnesses
and those who are subject to polypharmacy.
Prior to 1962, there were obviously many drugs that had
been on the market. What was to become of those whose
efficacy or safety had never been proven in any trials? In
1968 the FDA formed the Drug Efficacy Study Implementation (DESI) process to implement recommendations of
the National Academy of Sciences investigation of effectiveness of drugs first marketed between 1938 and 1962.
This then led to a series of drugs that by consensus underwent the DESI process and thus were considered acceptable and did not require any further study (1).
The Components of the FDA
The FDA consists of a highly motivated professional staff
of physicians, chemists, pharmacists, nurses, statisticians
(both mathematical and biostatisticians), lawyers, toxicologists, safety experts, mathematical modeling experts, and
Table 1. Structure of the Food and Drug Administration
Comissioner’s Office
Center for Drug Evaluation and Research
Office of New Drugs
Office of Drug Safety
Office of Compliance
Center for Biologics
Center for Cosmetics and Food
Center for Devices
Center for Veterinarian Medicines
administrative staff that are organized somewhat by discipline to serve the public health as regulators of available
drugs, foods, and cosmetics. The Code of Federal Regulations states that drugs are to be approved in the US for
improvement in how a patient feels, functions, or survives
(2,3). All other ways to measure therapeutic benefit need to
reflect these tenents in some fashion.
The organization chart reflects a hierarchical structure
with responsibility being assigned down the line as appropriate to level of training and experience. This structure is
generally reflected in the pay grade of the individual. The
Commissioner of the FDA is appointed by the White
House and is confirmed by the Senate. The appointee
usually sits in that role through the tenure of the current
denizen of the White House. The FDA is part of Health and
Human Services (HHS), so the Commissioner reports to
the Secretary of that Cabinet-level department and interacts significantly with HHS and the White House leadership (2). However, Congress controls the FDA budget, so
there is a careful political balancing act between the overall health care agenda set by the White House and the
public health needs as determined by Congress. Theoretically, the Commissioner should either be a professional as
an MD, PhD, or DVM, or at least be affiliated with the
health care field of either humans or animals. Our most
recent Commissioner was a veterinarian by training, and
his predecessor was an MD/PhD health economist.
The Commissioner serves to represent the FDA in front
of Congress regarding important policy issues as well as
the budget. There is a large supporting office consisting of
staff as well as deputy commissioners. There are 5 centers
at the FDA, each with a director (Table 1). The Center for
Drug Evaluation and Research has been the important
center for the approval of drugs and biologic therapeutics
since 2002, while the Center for Devices evaluates the
utility of joint implants, for example.
The Review Process
The reviews are carried out in the review division, which
consists of physicians, chemists, pharmacists, nurses, statisticians (both mathematical and biostatisticians), toxicologists, safety experts, mathematical modeling experts, and
administrative staff, all of whom are within a team format
(Table 2). The review division exists within the Office of
New Drugs, and each division has a director. The head of
the review team within a division is typically a medical
officer who performs a review of the evidence for safety
and efficacy along side the statistical reviewers who perform an in-depth analysis and reanalysis. Toxicologists
Table 2. Other review groups involved in new drug
application review
Review groups
Chemistry Review Team (manufacturing)
Microbiology Review Team (sterility assurance)
Statistical Review Team (clinical studies)
Biopharmaceutics Review Team (bioavailability)
Office of Drug Safety (safety profile)
Division of Drug Marketing, Advertising and
Communication (labeling)
Compliance (manufacturing site inspections)
Division of Scientific Investigations (clinical site
Division of Medication Errors and Technical Support
(trademark review)
review the nonclinical (preclinical) information, chemists
review the manufacturing processes, and biopharmaceutists review the pharmaceutical nature of the drug, including the pharmacokinetics and pharmacodynamics as they
are studied and understood. Interactions with the team are
governed by a project manager who also maintains contact
with the sponsor of a product and facilitates interactions
with the developer of the product and the internal review
team. These project managers are usually either pharmacists or nurses (4,5).
Because the FDA approves drugs for interstate transport
that have been determined, through the performance of
adequate and well-controlled trials, to be relatively safe for
the relative benefit of the approved indication determined
through this aforementioned review process, one might
ask when the first contact between a drug developer and
the FDA occurs. Once a company decides to develop a new
chemical or biologic entity, the company will request a
preinvestigational new drug (pre-IND) meeting. At this
meeting, plans are made to move forward with applying
for a pre-IND, which allows for interstate transport of
therapeutics that have not been approved but will need to
be shipped to allow studies to be conducted on the drug. If
there is little accumulated animal work using the drug to
be studied, then the timeline for all steps could be up to 14
years. If some of this work has been done, then the timeline until approval for some therapies might be as short as
9 years; however, some drugs might need up to 2- or 3-year
studies to be able to prove efficacy and safety. It might take
much longer to approve these drugs because a 2–3-year
study might actually take 1–2 years to fully recruit patients, and then the study might last for up to 6 years until
the last patient finishes the assigned protocol (5).
The drug development process is high risk and quite
expensive. Therefore, the drug developer is encouraged to
avail themselves of the opportunity to meet with the respective review division at specific time points to ensure
an orderly progression of accruing evidence of safety and
efficacy. The various sections of the process towards drug
development are listed in Table 3. The initial section is the
pre-IND meeting. At some point the animal exposure data
need to be discussed, including the maximally tolerated
dose, whether the drug’s mechanism of action can be evaluated in the animal or animal model of disease, and a
review of long-term animal exposure to those drugs that
would be predicted to be used chronically in humans.
These data are submitted to the final new drug application
of the biologic licensing application, but are also reviewed
as they are accrued. This is required because it is impossible to administer a study drug at any dose to a human,
single dose or dose escalating, prior to an extensive exposure experience in animals.
It is not unusual that much of this information will be
presented at a pre-IND meeting, but if it is not accrued at
that time then there will likely be another meeting arranged to discuss these data. Therefore, there are very few
drugs in development that are not known to the FDA. Once
an IND is established and a unique identifier assigned to
the product, the review division reviews each study as it is
initially designed and information about both animal experiences and human exposures are submitted periodically, for example, after studies are completed and safety
data are accrued and submitted in periodic safety update
reports. Once this period of study is completed, which
usually concerns both phase I and II studies of dose, dose
duration, and bioavailability and metabolism of the new
drug in humans, the developer of the drug then returns to
the review division for an end of phase II meeting. At this
time the developer discusses with the FDA the plans for
the phase III pivotal trials to allow for the accrual of data,
which will be the primary data used for the New Drug
Application (NDA) or Biologic Licensing Application
(BLA) allowing for subsequent registration and marketing
of the product if approved. This discussion is critical in
that the phase III program should be large enough for the
FDA to ultimately have enough data to understand relative
risk and relative benefit, as well as enough information
accrued from the potential completed data set to describe
how to use the new drug, its risks, its expected benefits,
and any approaches to manage the risk that would be
learned along the way. This information is what is printed
within the product label, which reflects the adjudicated,
unbiased evaluation of the totality of the evidence accrued
in the development program.
The total amount of expected patient exposure is deTable 3. Typical development program*
Animal data usually surrounding safety but efficacy
might be added in POC
Phase I
Usually safety, SAD, MAD, PK/PD, very short term
Phase II
Efficacy signal studied, dose ranging, may include
Longer than in phase I, some safety data accumulated
Phase III
More robust, larger numbers, and longer duration,
would serve as pivotal trials for approval
* POC ⫽ proof of concept; SAD ⫽ single ascending dose; MAD ⫽
multiple ascending doses; PK ⫽ pharmacokinetic; PD ⫽ pharmacodynamic; NDA ⫽ New Drug Application; BLA ⫽ Biologic Licensing
FDA Primer
Table 4. Action letters*
Not approvable
Lists deficiencies why application can not be approved
21 CFR 314.120
21 CFR 314.125
NDA can be approved, often with labeling changes and
phase IV study commitments
21 CFR 314.110
NDA is approved
21 CFR 314.105
* CFR ⫽ Code of Federal Regulations; NDA ⫽ New Drug
fined in a consensus document that is agreed to by many of
the regulatory bodies around the world. This “harmonization” document suggests that minimum exposure for a
drug meant for chronic use would be defined as a total of
1,500 patients with 100 patients exposed for 1 year, and
300 – 600 exposed for 6 months (6).
The phase III trials are then implemented, and once they
are completed and analyzed, the company returns to the
review division to once again gain insight into moving
forward with submitting all of the accumulated evidence
for review within their NDA or BLA. This pre-NDA or
pre-BLA meeting is a crucial piece of the pie.
Once submitted, the product is then reviewed as described below. Once the review takes place, the new product could be approved or not approved. In addition, the
product might be thought to be approvable, meaning it did
work but more information needs to be accrued or other
issues need to be clarified, or, as shown in Table 4, the
drug is not approvable.
It is poorly understood by the general community what
an actual review entails. A submission in electronic format
could be up to the equivalent of 1,000,000 pages of information. It is split into the appropriate sections according
to discipline, thus the chemists review the manufacturing
information as well as the proposed way in which the product will be stored and shipped, etc. The safety and efficacy
data are sent to the appropriate statisticians who actually
dissect the information using the submitted raw data and
often both check the submitted evidence and redo the analyses using both the method described by the drug developer
and other methods. Sensitivity analyses may also be performed to check the integrity of the data. The components of
the review outcome and the corresponding sections of the
Code of Federal Regulations are outlined in Table 5.
Because the organization of the FDA is hierarchical,
each discipline involved in a review team is represented
by the individual who is assigned the primary review for
that discipline (Table 2). This individual reports to a team
leader in that discipline who supervises the work. The
team leader then reports to either the deputy director of
the division or the division director, either of whom is
responsible for the review process of the team as a whole.
Not only is the team required to perform the review within
the parameters defined by the user fee process, but the
review is expected to be honest and quite rigorous to
withstand outside review; in my experience, this was always the case. These documents are then placed within
the permanent historical files of a division.
During the review process, the clinical research forms
are randomly evaluated for completeness and inspections
of the clinical sites where the studies were carried out are
performed to ensure that the appropriate review boards
were apprised of the studies, informed consent from the
patients was completed, and charts of the progress were
kept according to the expectations of good clinical practice. In multicenter trials as well as multicountry trials,
analyses are performed to be sure that there are no unusual
effects of the drugs in specific study centers or study countries that might have skewed the results. While this type of
work is pursued, the medical officer then proceeds to dissect
the safety analyses to ensure there is clear understanding of
the safety signals. Monthly progress meetings of the review
group are held with a general discussion as well as specific
reports on the progress of each discipline.
Once a decision is reached, the sponsor of a potentially
new therapeutic will receive a letter from the FDA. Table
4 outlines the types of letters. An approval letter will lead
to the subsequent marketing of a product, and will be
issued when the FDA has determined that the relative risk
to benefit warrants the marketing of a product and when
the label for that product is finished and approved by both
the sponsor and the FDA. Another answer might be that
the product is approvable, which suggests that there remain some questions but overall the therapeutic could be
marketed if these questions are answered. Finally, there is
the nonapproved letter, which fundamentally is issued
when there is clear evidence that the relative risk to relative benefit as shown in the submitted database does not
warrant marketing of the product at that time. These are
predicated on what is known about the product at the
time. Further study might allow that information to be
updated, and with subsequent submitted information the
decision might be changed.
At times, the FDA turns to outside experts who serve for
specified terms on Advisory Committees (7). These committees are constructed to be diverse as far as demographics, race, and sex so that they represent the expertise
throughout the country. There are 4-year terms of service,
and the individual who joins such a committee becomes a
special government employee and is governed in that role
by oversight from the Ethics groups at the FDA. The ethics
rules during the tenure of the committee member are not
terribly dissimilar from those that full employees have to
Table 5. New Drug Application review (focus)
Substantial evidence of effectiveness
“. . .Evidence consisting of adequate and wellcontrolled investigations, including clinical
investigations, by qualified scientific experts, that
proves the drug will have the effect claimed by its
labeling. . .” (Kefauver-Harris Drug Amendments to
Section 505[d] of Federal Food, Drug and Cosmetic
Act, 1962)
Safety (Federal Food, Drug and Cosmetic Act of 1938)
Labeling (Original Food & Drug Act of 1906)
follow. The advisory committee might meet to discuss
particular drugs under review; to review policy or deal
with the development of guidances, which serve as roadmaps delineating a path for drug development; or even to
meet behind closed doors to review proprietary information about a product or sponsor.
The Way the FDA Works
The daily work plan typically includes some aspect of
work dedicated to the evaluation of a new drug application. The work plan also includes reviewing periodic
safety updates that are submitted for drugs previously
approved for marketing by the medical officer, which then
have to be followed for the life of the drug; reviewing new
investigational new drug applications; answering queries
and consults regarding products under review from other
divisions; reviewing policy and procedural changes; participating in educational programs ranging from statistical
analysis programs to how to write reviews; and participating in organizational meetings of the division as well as
the office. In addition, the work day is ⬃8 hours, with an
⬃40-hour work week. The employee is not able to hold
another job or “moonlight” without permission, regardless
of when that work might take place. All outside income
must be vetted and reviewed by the ethics group at the
FDA to ensure that there are no perceived conflicts of
interest. In fact, there are limited opportunities to actually
participate in outside professional activities, and the medical officers are urged to develop some liaison with an
outside hospital or clinic so that they can participate in
periodic medical care as might be practicable. This development time is critical to allow the medical officer to
“keep their hands in” and allow them to maintain some
perspective regarding the practice of medicine. This time
is usually for half a day per week, but at times that can be
significantly increased. The medical officer donates this
time to the practice site while continuing to be paid by the
Much has been said about potential conflicts of interest,
which is really unrealistic. The PDUFA user fee system
has allowed for increased numbers of medical officers to
perform the review function and participate in all of the
other duties. The fact that a fee is paid for a review is not
appreciated directly by a division or reviewer. Furthermore, the reviewers are all very dedicated to their jobs and
the work that they do. There is a very rigorous ethical
review of each employee on a regular basis that evaluates
all sources of income and investment holdings. No employee or anyone in that employee’s family can receive
any type of income from any source whose activities are
overseen by the FDA.
Postmarketing Surveillance
Although a significant amount of time and energy is spent
reviewing new therapeutics before approval for relative
risk to relative benefit, it should not be forgotten that this
benefit-to-risk balance is truly understood by observing
more real world use of a drug than use in randomized
controlled trials. This is accomplished once a drug is marketed. At that point more heterogeneous groups of patients
are exposed, including patients with comorbid illnesses
who often are using other concomitant therapies. This type
of information is gained by facilitated postmarketing reports that are submitted by the sponsor of a product, or
through the voluntary MedWatch or Adverse Event Reporting System (AERS) maintained by the FDA. There are
⬃300,000 MedWatch reports submitted about all therapies
approved in the US per year. These are reviewed and
correlated with other international reports, and lead to
complex risk analyses that are considered by the Office of
Drug Safety (FDA) along with the individual and appropriate Review Divisions. There is an attempt to understand
the overall risk and benefit by reviewing both premarketing and postmarketing experiences. The premarketing experiences often allow hazard rates to be determined in that
trials have denominators of patients exposed, whereas in
the postmarketing realm, the number of prescriptions of a
certain product is known but how many patients may take
a therapeutic needs to be approximated. Therefore, the
postmarketing data are somewhat more inferential than
the clinical studies.
Other data sets can be reviewed to help supplement the
accumulated data from the AERS data set. These sources
can be from registries, cohort studies, and managed care
organizations. Unfortunately, these approaches provide
signals of potential problems; however, due to a lack of
randomization as to how a patient receives one versus
another therapeutic, channeling bias may decrease the
utility of these observations. Nonetheless, these data along
with the previously accumulated pre- and postmarketing
data may provide a robust window into the risk of any
particular therapeutic. All of these data are used to determine the importance of continued marketing of a product.
This level of scrutiny is constant throughout the life cycle
of any product in the US.
The process of regulatory oversight is one that needs to be
detail oriented and rigorous. Presently, despite recent media coverage, the FDA is quite well constructed to provide
robust and careful regulatory oversight of the development
of therapeutics. I urge everyone interested in providing the
best possible care to their patients to take advantage of the
FDA Web site (2) as well as the product labels to learn the
best and unbiased appropriately adjudicated evidence
published about therapies.
1. US Food and Drug Administration. A brief history of the Center
for Drug Evaluation and Research. URL:
2. US Food and Drug Administration. URL:
3. US Food and Drug Administration. Food, Drug and Cosmetic
Act. USC Title 21 Chapter 9. Amended December 31, 2004.
4. US Food and Drug Administration. The CDER handbook. URL:
5. Tamar Nordenberg. Inside FDA: The Center for Drug Evaluation and Research. US Food and Drug Administration. URL:
6. US Food and Drug Administration. International harmonization. URL:
7. US Food and Drug Administration. FDA advisory committees.